Neuroprotective indolone and related derivatives

ABSTRACT

5-(1-Hydroxy-2-piperidinopropyl)-2(1H,3H)-indolone derivatives and analogs; pharmaceutical compositions thereof; methods of treating CNS disorders therewith; and intermediates useful in the preparation of said compounds.

BACKGROUND OF THE INVENTION

The present invention is directed to neuroprotective (antiischemic andexcitatory aminoacid receptor blocking)5-(1-hydroxy-2-piperidinopropyl)-2(1H,3H) -indolone analogs, defined bythe formula (I), (II) and (III) below; pharmaceutically acceptable saltsthereof; a method of using these compounds in the treatment of stroke,traumatic brain injury or CNS degenerative diseases such as Alzheimer'sdisease, senile dementia of the Alzheimer's type, Huntington's diseaseand Parkinson's disease; and to certain intermediates therefor.

Ifenprodil is a racemic, so-called dl-erythro compound having therelative stereochemical formula ##STR1## which is marketed as ahypotensive agent, a utility shared by a number of close analogs; Carronet al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp.1992-1999 (1971). Ifenprodil has also been shown to possess antiischemicand excitatory aminoacid receptor blocking activity; Gotti et al., J.Pharm. Exp. Therap., v. 247, pp. 1211-21 (1988); Carter et al., loc.cit., pp. 1222-32 (1988). See also published European patent application322,361 and French Patent 2546166. A goal, substantially met by thepresent invention, has been to find compounds possessing suchneuroprotective effect in good measure, while at the same time havinglowered or no significant hypotensive effect.

Certain structurally related 1-phenyl-3-(4-aryl-4-acyloxypiperidino)-1-propanols have also been reported to be usefulas analgesics, U.S. Pat. No. 3,294,804; and 1-[4-(amino- andhydroxy-alkyl)phenyl]-2-(4-hydroxy -4-tolylpiperazino)-1-alkanols andalkanones have been reported to possess analgesic, antihypertensive,psychotropic or antiinflammatory activity, Japanese Kokai 53-02,474 (CA89:43498y; Derwent Abs. 14858A), 53-59,675 (CA 89:146938w; Derwent Abs.48671A) and 76,118,772 (CA 86:189738m).

More recently, in published European Patent Application No. 351,282,compounds which include those of the formula ##STR2## wherein R^(a) andR^(b) are each independently hydrogen or (C₁ -C₄)alkyl, R^(c) is benzyl,phenoxy, benzyloxy or phenoxymethyl, and Z^(a) is CH₂, C(CH₃)₂ or CH₂CH₂, have been reported as having neuroprotective type activity.

Also, amino ketone and amino alcohol derivatives of benzoxazolinone andtheir adrenergic and antihypertensive properties are described in theEuropean Journal of Medicinal Chemistry, 25, 361-368, (1990), C.A.113:191213f.

The nomenclature used herein is generally that of Rigaudy et al., IUPACNomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, NewYork. 2(1H,3H)-Indolones are alternatively named as oxindoles.

SUMMARY OF THE INVENTION

The present invention is directed to racemic or optically activecompounds of the formulas ##STR3## n is 0 or 1; m is 0 or an integerfrom 1-6;

R, R¹ and R² are each independently hydrogen or (C₁ -C₃)alkyl;

R³ and R⁴ are taken separately and are each hydrogen, or R³ and R⁴ aretaken together and are ethylene;

X is hydrogen, (C₁ -C₃)alkoxy]-carbonyl;

Y is CH₂ or oxygen;

Z and Z¹ are each independently hydrogen, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy,fluoro, chloro or bromo;

and the pharmaceutically-acceptable acid addition salts thereof.

The preferred compounds of the present invention generally have R² ashydrogen or methyl, most preferably as methyl, having relativestereochemistry in 1-hydroxypropyl side chain depicted as ##STR4## andwhich is specified either as (1S^(*),2S^(*)) or (1R^(*),2R^(*)).

The preferred values of A are generally ##STR5##

The present invention is also directed to intermediate compounds of theformula ##STR6## wherein the variable groups are as defined above.

The present invention is further directed to pharmaceutical compositionscomprising a compound of the formula (I), (II) or (III), and to a methodof treating stroke, traumatic brain injury or a CNS degenerative diseasewith a compound of the formula (I), (II) or (III).

The expression "pharmaceutically-acceptable acid addition salts" isintended to include but is not limited to such salts as thehydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate,dihydrogen phosphate, mesylate, maleate and succinate. Such salts areconventionally prepared by reacting the free base form of the compound(I), (II) or (III) with an appropriate acid, usually one molarequivalent, and in a solvent. Those salts which do not precipitatedirectly are generally isolated by concentration of the solvent and/oraddition of a non-solvent.

It will be noted that those compounds of the formula (I) to (VI) which,in the central portion of the molecule, are 1-alkanols possess anasymmetric C-1 carbon, while those wherein R is other than hydrogenpossess a second asymmetric center at the C-2 carbon of the alkanol.Similarly, in those compounds of the formulas (IV) to (VI) which are1-alkanones wherein R is other than hydrogen possess a C-2 asymmetriccarbon. It will be evident to those skilled in the art of organicchemistry, therefore, that such compounds can be resolved into opticalisomers showing equal but opposite rotation of plane polarized light.For example, all of these compounds are potentially resolved byfractional crystallization of their diastereomeric addition salts withan optically active acid, as exemplified below. The alcohols are alsopotentially resolved by chromatography or fractional crystallization ofesters or urethanes derived by reaction with activated forms ofoptically active acids or with optically active isocyanates, as alsoexemplified below. Thus, the present invention should not be construedas limited to the racemic forms of the present compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention, having the formula (I), (II) and(III) defined above, are readily prepared.

The precursor ketones are generally prepared by nucleophilicdisplacement of an appropriately substituted 2-halo,2-alkanesulfonyloxy- or 2-arylsulfonyloxy -1-alkanone with anappropriately substituted piperidine derivative, e.g., ##STR7## whereinX is typically chloro, bromo, mesyloxy or tosyloxy. This reaction iscarried out under conditions typical of nucleophilic displacements ingeneral. Where the two reactants are about equivalent in availability,close to substantially molar equivalents may be used; although when oneis more readily available, it is usually preferred to use that one inexcess, in order to force this bimolecular reaction to completion in ashorter period of time. The reaction is generally carried out in thepresence of at least 1 molar equivalent of a base, the piperidinederivative itself, if it is readily available, but more usually atertiary amine which is at least comparable in base strength to thenucleophilic piperidine; and in a reaction inert solvent such asethanol. If desired, the reaction is catalyzed by the addition by theaddition of up to one molar equivalent or more of an iodide salt (e.g.,NaI, KI). Temperature is not critical, but will generally be somewhatelevated in order to force the reaction to completion within a shortertime period, but not so high as to lead to undue decomposition. Atemperature in the range of 50°-120° C. is generally satisfactory.Conveniently, the temperature is the reflux temperature of the reactionmixture.

As used in the preceding paragraph, and elsewhere herein, the expression"reaction inert solvent" refers to any solvent which does not interactwith starting materials, reagents, intermediates or products in a mannerwhich adversely affects the yield of the desired product.

The resulting ketone intermediates are conveniently converted tocorresponding alcohols by conventional reduction with NaBH₄, usually inexcess, in a protic solvent such as methanol or ethanol, generally attemperature in the range of about 15°-45° C.

The starting materials and reagents required for the synthesis of thecompounds of the present invention are readily available, eithercommercially, according to literature methods, or by methods exemplifiedin Preparations below.

The present compounds of the formula (I), (II) and (III) possessselective neuroprotective activity, based upon their antiischemicactivity and ability to block excitatory aminoacid receptors, while atthe same time generally having lowered or no significant hypotensiveactivity. The antiischemic activity of the present compounds isdetermined according to one or more of the methods which have beendetailed previously by Gotti et al. and Carter et al. cited above, or bysimilar methods. The ability of the compounds of the Present inventionto block excitatory amino acid receptors is demonstrated by theirability to block N-methyl-D-aspartic acid-induced (NMDA) elevations ofcGMP in neonatal rat cerebellums according to the following procedure.Cerebellums from ten 8-14 day old Wistar rats are quickly excised andplaced in 4° C. Krebs/bicarbonate buffer, pH 7.4 and then chopped in 0.5mm×0.5 mm sections using a McIlvain tissue chopper (The NickleLaboratory Engineering Co., Gomshall, Surrey, England). The resultingpieces of cerebellum are transferred to 100 ml of Krebs/bicarbonatebuffer at 37° C. which is continuously equilibrated with 95:5 O₂ /CO₂.The pieces of cerebellum are incubated in such a manner for ninetyminutes with three changes of the buffer. The buffer then is decanted,the tissue centrifuged (1 min., 3200 r.p.m.) and the tissue resuspendedin 20 ml of the Krebs/bicarbonate buffer. Then, 250 μl aliquots(approximately 2 mg) are removed and placed in 1.5 ml microfuge tubes.To those tubes are added 10 μl of the compound under study from a stocksolution followed, after a 10 minute incubation period, by 10 μl of a2.5 mM solution of NMDA to start the reaction. The final NMDAconcentration is 100 μM. Controls do not have NMDA added. The tubes areincubated for one minute at 3? ° C. in a shaking water bath and then 750μl of a 50 mM Tris-Cl, 5 mM EDTA solution is added to stop the reaction.The tubes are Placed immediately in a boiling water bath for fiveminutes. The contents of each tube then are sonicated for 15 secondsusing a probe sonicator set at power level three. Ten microliters areremoved and the protein determined by the method of Lowry, Anal.Biochem. 100:201-220 (1979). The tubes are then centrifuged (5 min.,10,000 xg), 100 μl of the supernatant is removed and the level of cyclicGMP (cGMP) is assayed using a New England Nuclear (Boston,Massachusetts) cGMP RIA assay according to the method of the supplier.The data is reported as pmole cGMP generated Per mg. protein. Undesiredhypotensive activity is also determined by known methods, for example,according to the methods of Carron et al., also cited above.

Such selective neuroprotective antiischemic and excitatory amino acidblocking activities reflect the valuable utility of the presentcompounds in the treatment of stroke, traumatic brain injury anddegenerative CNS (central nervous system) disorders such as Alzheimer'sdisease, senile dementia of the Alzheimer's type, Parkinson's diseaseand Huntington's disease; without significant potential for aconcurrent, undue drop in blood pressure. In the systemic treatment ofsuch diseases with a neuroprotective amount of compounds of the formula(I), (II) or (III), the dosage is typically from about 0.02 to 10mg/kg/day (1-500 mg/day in a typical human weighing 50 kg) in single ordivided doses, regardless of the route of administration. 0f course,depending upon the exact compound and the exact nature of the individualillness, doses outside this range may be prescribed by the attendingphysician. The oral route of administration is generally preferred.However, if the patient is unable to swallow, or oral absorption isotherwise impaired, the preferred route of administration will beparenteral (i.m., i.v.) or topical.

The compounds of the present invention are generally administered in theform of pharmaceutical compositions comprising at least one of thecompounds of the formula (I), (II) or (III), together with apharmaceutically acceptable vehicle or diluent. Such compositions aregenerally formulated in a conventional manner utilizing solid or liquidvehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, manner utilizing solid orliquid vehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, powders and the like; forparenteral administration, in the form of injectable solutions orsuspensions, and the like; and for topical administration, in the formof solutions, lotions, ointments, salves and the like.

The present invention is illustrated by the following examples, but isnot limited to the details thereof.

EXAMPLE 1 5-[2-(4-Benzyl-4-hydroxypiperidino)propionyl]-2(1H,3H)-indolone

5-(2-Chloropropionyl)-2(1H,3H)-indolone (2.5 g, 11.2 mmol),4-hydroxy-4-benzylpiperidine (2.1 g, 11.2 mmol), and triethylamine (1.56ml, 11.2 mmol) were combined in ethanol and refluxed overnight. Themixture was cooled to room temperature and concentrated at reducedpressure. The residue was partitioned between ethyl acetate and waterand the phases were separated. The aqueous layer was extracted withethyl acetate and the combined organic phase was washed with brine,dried over calcium sulfate, and concentrated. The crude product wasflash chromatographed on silica gel eluting first unreacted5-(2-chloropropionyl) -2(1H,3H)-indolone with 1:1 ethyl acetate:hexane.Continued elution with ethyl acetate gave 3.6 g of product as a lightbrown foam. Recrystallization from ethyl acetate/hexane gave 1.23 g ofpurified title product. Less pure fractions from the column and motherliquors from the recrystallization were rechromatographed as above with1:1 and then 3:1 ethyl acetate:hexane. Product fractions were trituratedwith ether/hexane to give 0.2 g more product for a total yield of 1.43g, 34%; m.p. 188°-192° C.; NMR 8.22 (s, 1H), 8.08 (d, J=8 Hz, 2H), 7.99(s, 1H), 7.31-7.13 (m, 5H), 6.89 (d, J=8 Hz, 1H), 4.03 (q, J=6.8 Hz,1H), 3.57 (s, 2H), 2.72 (s, 2H), 2.72-2.58 (m, 3H), 2.46 (distorted t,1H), 75-1.40 m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.23-1.19 (m, 1H).

Anal. calcd for C₂₃ H₂₆ N₂ O₃ : C, 72.99; H, 6.92; N, 7.40%.

Found: C, 72.68; H, 6.77; N, 7.28%.

EXAMPLE 2 5-[2S^(*) -(4-Benzyl-4-hydroxypiperidino) -1S^(*)-hydroxypropyl]-2(1H,3H)-indolone

The product from Example 1 (0.75 g, 1.98 mmol) was dissolved in 50 ml ofhot ethanol and allowed to cool. The solution was added over 1-2 minutesto a slurry of sodium borohydride (0.113 g, 2.98 mmol) in ethanol (50ml) with a 25 ml ethanol rinse. The mixture was stirred overnight. Water(2 ml) was added and the solvent was removed at reduced pressure. Theresidue was partitioned between ethyl acetate and water. Note that asmall amount of dithionite was added to all aqueous washes to preventair oxidation of the product. The organic layer was separated, washedwith brine, dried over calcium sulfate and concentrated to a whitesolid. This material was recrystallized from ethanol to give 0.24 g ofproduct. The mother liquors were flash chromatographed on silica gelwith ethyl acetate elution to afford 0.19 g more product for a totalyield of 0.43 g, 57%; m.p. 228°-229° C. NMR 7.66 (br s, 1H), 7.31-7.10(m, 7H), 6.77 (d, J=8 Hz, 1H), 4.17 (d, J=10 Hz, 1H), 3.49 (s, 2H), 2.84(dt, J=2.5, 11 Hz, 1H), 2.76 (s, 2H), 2.65-2.40 (m, 4H), 1.86-1.50 (m,5H), 1.15 (s, 1H), 0.76 (d, J=6.5 Hz, 3H).

Anal. calcd for C₂₃ H₂₈ N₂ O₃ : C, 72.61; H, 7.42; N, 7.36%.

Found: C, 73.04; H, 7.50; N, 7.35%.

EXAMPLE 3 5-[2S^(*) -(4-Hydroxy-4-phenylpiperidino) -1S^(*)-hydroxypropyl]-2(1H,3H)-indolone

By the procedures of Examples 1 and 2, 4-hydroxy-4-phenylpiperidine wasconverted to present title product in 38% over-all yield. The productwas purified by silica gel flash chromatography and trituration withethyl acetate; m.p. 216°-218° C.; NMR 7.51 d, J=9 Hz, 3H--has NH protonin this signal), 7.36 (t, J=7.5 Hz, 2H), 7.24 (dt, J=1.2, 7.5 Hz, 2H),7.17 (dd, J=1.2, 7.5 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 4.22 (d, J=10 Hz,1H), 3.51 (s, 2H), 3.08 (dt, J=2, 11 Hz, 1H), 2.7-2.48 (m, 5H),2.24-1.98 (m, 2H), 1.83-1.70 br d, 2H), 1.49 (s, 1H), 0.82 (d, J=7 Hz,3H).

Anal. calcd for C₂₂ H₂₆ N₂ O₃ : C, 72.11; H, 7.15; N, 7.64%.

Found: C, 72.23; H, 7.30; N, 7.30%.

EXAMPLE 4 5-[2S^(*) -(4-Hydroxy-4-phenylpiperidino) -1S^(*)-hydroxypropyl]-3-methyl-2(1H,3H)-indolone

By the method of Examples 1 and 2,5-(2-chloropropionyl)-3-methyl-2(1H,3H)-indolone and 4-hydroxy-4-phenylpiperidine were converted to present title product in 24%yield; m.p. 219°-220° C. (from ethyl acetate).

EXAMPLE 5 5-[2-(4-Hydroxy-4-phenylpiperidino)propionyl]-1-(p-toluenesulfonyl)indole

5-(2-Bromopropionyl)-1-(p-toluenesulfonyl)indole (1.67 g, 3.37 mmol, 83%purity) was dissolved in hot ethanol (100 ml) and4-hydroxy-4-phenylpiperidine (0.6 g, 3.39 mmol) and triethylamine (0.94ml, 6.74 mmol) were added. The mixture was refluxed overnight. Thereaction was cooled and concentrated directly onto silica gel and flashchromatographed. Elution with 1:3 ethyl acetate:hexane removed 0.1 g ofnon-brominated ketone. Continued elution with 1:1 ethyl acetate hexanegave 1.47 g, 87% of the title product as a glassy orange solid. NMR 8.34(s, 1H), 8.09 (d, J=9 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5Hz, 2H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.33-7.29 (m,2H), 7.24-7.21 (m, 4H), 6.72 (d, J=3.5 Hz, 1H), 4.18 (q, J=7 Hz, 1H),2.88-2.84 (m, 2H), 2.73-2.62 (m, 2H), 2.32 (s, 3H), 2.18-2.06 (m, 1H),2.05-1.97 (m, 1H), 1.77-1.66 (m, 1H), 1.59-1.54 (m, 1H), 1.31 (d, J=7Hz, 3H). IR 1679, 1605, 1375, 1289, 1260, 1169, 1126, 994. FAB HRMScalcd for C₂₉ H₃₁ N₂ O₄ S (MH⁺): 503.2006. Observed m/e: 503.2023.

EXAMPLE 6 5-[2-(4-Hydroxy-4-phenylpiperidino)propionyl]indole

The product of the preceding Example (1.3 g, 2.75 mmol) was dissolved inmethanol (50 ml) and potassium hydroxide (0.324 g, 5.79 mmol) was addedall at once. The mixture was refluxed 6 hours, then cooled and thesolvent removed at reduced pressure. The residue was partitioned betweenethyl acetate and water. The phases were separated and the aqueous layerwas extracted with ethyl acetate. The combined organic layer was washedwith brine, dried over calcium sulfate and concentrated. The residue wasflash chromatographed on silica gel with 1:1 ethyl acetate:hexaneelution to give 0.719 g, 75% of present title product as a glassy solid;m.p. 60°-70° C. NMR 8.52 (s, 1H), 8.49 (br s, 1H), 8.00 (dd, J=1.5, 8.5Hz, 1H), 7.49-7.41 (m, 3H), 7.35-7.21 (m, 4H), 6.67 (s, 1H), 4.30 (q,J=6.5 Hz, 1H), 2.89-2.85 (m, 3H), 2.66 (t, J=9.5 Hz, 1H), 2.23-2.07 (m,2H), 1.77-1.65 (m, 2H), 1.38 (d, J=6.5 Hz, 3H). IR(CHCl₃) 3470, 2924,1673, 1613, 1412, 1348, 1323, 1276, 1224, 1115. FAB HRMS calcd for C₂₂H₂₅ N₂ O₄ (MH+ ): 349.1918. Cbserved m/e: 349.1930.

EXAMPLE 7 5-[2S^(*) -(4-Hydroxy-4-phenylpiperidino) -1S^(*)-hydroxypropyl]indole

The product of the preceding Example was reduced according to theprocedure of Example 2. Present title product was obtained as a fluffywhite solid in 15% yield after silica gel chromatography andrecrystallization from ethanol; m.p. 220.5°-221° C. NMR 8.16 (br s, 1H),7.63 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 3H), 7.30-7.19(m, 3H), 6.53 (s, 1H), 4.39 (d, J=10 Hz, 1H), 3.08 (dt, J=2, 11.5 Hz,1H), 2.90-2.62 (m, 4H), 2.35-2.10 (m, 2H), 1.90-1.80 (m, 2H), 0.82 (d,J=6.5 Hz, 3H). IR(CHCl₃) 3475, 2922, 1731, 1376, 1250, 1201, 1038.

Anal. calcd for C₂₂ H₂₆ N₂ O₂ : C, 75.40; H, 7.48; N, 7.99%.

Found: C, 74.99; H, 7.47; N, 7.91%.

EXAMPLE 8 5-[2-(4-Benzyl-4-hydroxypiperidino)acetyl]-2(1H,3H)-indolone

A mixture of 5-(chloroacetyl)-2(1H,3H)-indolone (2.05 g, 9.78 mmol),4-hydroxy-4-benzylpiperidine (1.87 g, 9.78 mmol), potassium carbonate(2.97 g, 21.49 mmol), and potassium iodide (0.08 g, 0.48 mmol) inacetonitrile (200 ml) was refluxed overnight. The reaction was cooledand filtered through a celite pad. The filtrate was concentrated to givean orange foam which was flash chromatographed on silica gel with ethylacetate elution. This afforded 0.79 g of oily yellow solid product. NMR9.41 (br s, 1H), 7.91 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.28-7.14 (m, 5H),6.90 d, J=8 Hz, 1H), 3.76 (s, 2H), 3.52 (s, 2H), 2.78-2.73 (m, 4H), 2.43{t, J=10.5 Hz, 2H}, 1.86-1.76 (m, 2H), 1.50 (br d, J=12 Hz, 2H), 1.36(br s, 1H). IR(KBr) 2920, 2815, 1710, 1685, 1615, 1240, 1115. FAB HRMScalcd for C₂₂ H₂₅ N₂ O₃ (MH⁺): 365.1867. Observed m/e: 365.1883.

EXAMPLE 9 5-[2-(4-Benzyl-4-hydroxypiperidino)-1-hydroxyethyl]-2(1H,3H)-indolone

Reduction was carried out on the product of the preceding Exampleaccording to the procedure of Example 2. The product was purified byflash chromatography and recrystallization from ethyl acetate to yieldpresent title product as a tan solid in 18% yield; m.p. 168.5°-169.5° C.NMR 8.40 (br s, 1H), 7.35-7.17 (m, 7H), 6.80 (d, J=8 Hz, 1H), 4.66 (dd,J=3.5, 10 Hz, 1H), 3.50 (s, 2H), 2.89 (br d, J=11 Hz, 1H), 2.77 (s, 2H),2.68-2.33 (m, 6H), 1.83-1.67 (m, 2H), 1.59-1.52 (m, 2H), 1.27 (br s,1H). IR(KBr) 3420, 3170, 2945, 2820, 1705, 1625, 1490, 1320, 1115, 830,707. FAB HRMS calcd for C₂₂ H₂₇ N₂ O₃ (MH⁺): 367.2023. Observed m/e:367.2061.

EXAMPLE 10 5-[2-(4-Hydroxy-4-phenylpiperidino)-1-hydroxyethyl]-2(1H,3H)-indolone

By the procedures of Examples 8 and 2, 4-hydroxy -4-phenylpiperidine wasconverted to present title product in 5% yield after flashchromatography and repeated recrystallization from methylenechloride/ether; m.p. 192°-194° C. IR(KBr) 3410, 3180, 2930, 2825, 1715,1490, 705.

Anal. calcd for C₂₁ H₂₄ N₂ O₃ ·0.5 H₂ O: C, 69.79; H, 6.97; N, 7.75%.

Found: C, 69.77; H, 6.52; N, 7.60%.

EXAMPLE 11 6-[2-(4-Hydroxy-4-phenylpiperidino)-1-hydroxyethyl]-2(3H)-benzoxazolone

By the procedures of Examples 8 and 2,6-(2-chloroacetyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidinewere converted to present title product in 25% yield afterrecrystallization from ethanol/ether; m.p. 175°-177° C. NMR(methanol-d₄) 7.51 (dd, J=1.5, 8.5 Hz, 2H), 7.35-7.29 (m, 3H), 7.24-7.19(m, 2H), 7.05 (d, J=8 Hz, 1H), 4.94-4.90 (m, 1H--becomes dd J=3, 8.5 Hzwith D₂ O wash), 2.96-2.90 (m, 2H), 2.80-2.57 (m, 4H), 2.19 (dq, J=4.5,13 Hz, 2H), 1.74 (br d, J=14.5 Hz, 2H). IR(KBr) 3320, 3115, 2920, 2830,1785, 1750.

EXAMPLE 12 6-[2S^(*) -(4-Hydroxy-4-phenylpiperidino)-1S^(*)-hydroxypropyl)-3,4-dihydro-2(1H)-quinolone

By the procedures of Examples 1 and 2,5-(2-chloropropionyl)-3,4-dihydro-2(1H)-quinolone and 4-hydroxy-4-phenylpiperidine were converted to present title product obtained asa white solid in 28% yield after flash chromatography and ethyl acetaterecrystallization; m.p. 218°-219° C. NMR 7.92 (s, 1H), 7.52 (d, J=7.5Hz, 2H), 7.38 (t, J=7.5 Hz, 2H), 7.28 (t partially obscured by NMRsolvent peak, J=7 Hz, 1H), 7.20 (s, 1H), 7.14 (d, J=8 Hz, 1H), 6.70 (d,J=8 Hz, 1H), 5.27 (br s, 1H), 4.22 (d, J=10 Hz, 1H), 3.09 (t, J=11 Hz,1H), 2.96 (t, J=7 Hz, 2H), 2.73-2.58 (m, 6H), 2.32-2.05 (m, 2 H), 1.86(br d, J=14 Hz, 2H), 1.57 (s, 1H), 0.84 (d, J=6.5 Hz, 3H).

Anal. calcd for C₂₃ H₂₈ N₂ O₃ : C, 72.60; H, 7.42; N, 7.36%.

Found: C, 72.16; H, 7.34; N, 7.29%.

EXAMPLE 13 5-[2S^(*) -(3-(4-Chlorophenylthio)-8-azabicyclo[3.2.1]-oct-8-yl)-1S^(*) -hydroxypropyl]-2(1H,3H)-indolone

By the procedures of Examples 1 and 2,3-(4-chlorophenylthio)-8-azabicyclo[3.2.1]octane was converted topresent, ether triturated title product in 7% yield as a 1:1 mixturewith the corresponding lR^(*),2S^(*) -isomer; m.p. 146°-158° C.

EXAMPLE 14 6-[2S^(*) -(3-Phenylthio-8-azabicyclo[3.2.1]oct-8-yl) -1S-hydroxypropyl]-3,4-dihydro-2(1H)-quinolone

By the procedures of Examples 1 and 2,6-(2-chloropropionyl)-3,4-dihydro-2(1H)-quinolone and 3-phenylthio8-azabicyclo[3.2.1]octane were converted to present title product in 15%yield, m.p. 144°-145° C. (from ethyl acetate).

EXAMPLE 15 5-Chloro-6-[2R^(*) -(4-hydroxy-4-phenylpiperidino) -1S^(*)-hydroxypropyl]-2(3H)-benzoxazolone

By the procedures of Examples 1 and 2, 5-chloro-6-(2-chloropropionyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidine were converted to present title product in 79%yield; m.p. 198°-199° C. (from ethanol).

EXAMPLE 16 5-[2S^(*)-(3-Hydroxy-3-phenyl-8-azabicyclo[3.2.1]-oct-8-yl)-1S^(*)-hydroxypropyl]-2(1H,3H)-indolone

By the procedures of Examples 1 and 2, 3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]octane is converted to present titleproduct.

EXAMPLE 17 5-[2S^(*)-(3-Benzyl-3-hydroxy-8-azabicyclo[3.2.1]-oct-8-yl)-1S^(*)-hydroxypropyl]-2(1H,3H)-indolone

By the procedures of Examples 1 and 2, 3-benzyl-3-hydroxy-8-azabicyclo[3.2.1]octane is converted to present titleproduct.

EXAMPLE 18 Optical Resolution of 5-[2S^(*) -(4-Hydroxy-4-phenylpiperidino)-1S^(*) -hydroxypropyl]-2(1H,3H)-indolone Method A

A mixture of (+) camphor sulfonic acid (232 mg, 1 mmol) and titleproduct of Example 3 (366 mg, 1 mmol) was stirred in 25 ml of ethanol. Aclear homogeneous solution was nearly obtained before the salt began toprecipitate. After standing at ambient temperature overnight, the saltwas collected, rinsed with ethanol and dried under a stream of nitrogen.The 460 mg of pink salt obtained in this manner was recrystallized fromethanol four times. The resulting product weighed 260 mg, and had m.p.241°-242.5° C. and [α]_(Na) =+19.0° (c=0.295, methanol), indicating thatit was only partially resolved.

Method B

To a mixture of CH₂ Cl₂ (25 ml) and DMF (1 ml) were added title productof Example 3 (0.366 g, 1 mmol), dicyclohexyl carbodiimide (0.226 g, 1.1mmol), 1-hydroxybenzotriazole (0.148 g, 1.1 mmol),4-dimethylaminopyridine (0.134 g, 1.1 mmol), andN-tert-butyloxycarbonyl-L-alanine (0.189 g, 1 mmol). The mixture wasstirred under a nitrogen atmosphere overnight. The homogeneous solutionwas diluted with ethyl acetate (25 ml) and filtered through Celite (TM)to remove dicyclohexyl urea. The filtrate was concentrated and taken upin ethyl acetate (150 ml). A second filtration removed still moreurea-by-product. The filtrate was washed with aqueous bicarbonate, water1N aqueous LiCl and brine. The organic phase was dried over calciumsulfate and concentrated to an oily foam. Flash chromatography on silicagel (50×100 mm (2×4 inches) packed with 50% ethyl acetate/hexane) gaveupon elution with 75% ethyl acetate/hexane first 0.1 g of a nearly purediastereomer of the alanine adduct. This was followed by 0.2 g of amixture of the diastereomers and finally 0.1 g of a partially enrichedsample of the other diastereomer. The 0.2 g sample was rechromatographedin the same fashion to afford another 0.06 g of the first purediastereomer. The combined 0.16 g product was recrystallized from ethylacetate/hexane to give 0.094 g of the adduct as a white solid; m.p.189°-190° C. NMR (CDCl₃) 7 61 (br s, 1H--D₂ O washes out), 7.48 (dd,J=I.5, 8 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.34-7.18 (m, 3H), 6.83 (d,J=8 Hz, 1H), 5.76 (d, J=10 Hz, 1H), 5.19 (br d, J=7 Hz, 1H), 4.37 (br t,J=7 Hz, 1H), 3.54 (s, 2H), 3.06-2.90 (m, 2H), 2.84-2.52 (m, 3H),2.16-1.88 (m, 2H), 1.82-1.69 (m, 2H), 1.52 (d, J=7 Hz, 3H), I.40 (s,9H), 0.78 (d, J=7 Hz, 3H). [α]_(D) =+69.5°, c=0.295 in methanol.

Analysis calculated for C₃₀ H₃₉ N₃ O₆ : C, 67.02; H, 7.31; N, 7.82.

Found: C, 66.92; H, 7.46; N, 7.80.

This t-boc-alanine adduct (0.047 g, 0.087 mmol) was dissolved in 9 ml ofa 0.32N solution of sodium methoxide (0.15 g of Na dissolved in 20 ml ofmethanol). The mixture was stirred 2 hours and the solvent was removedat ambient temperature under vacuum. The residue was taken up in ethylacetate and extracted with aqueous bicarbonate and brine. The organicphase was dried over calcium sulfate and concentrated. The crude productwas flash chromatographed on silica gel (1×2 inches). After flushing thecolumn with 50% ethyl acetate/hexane, the fully resolved dextrorotatoryproduct was eluted with ethyl acetate; 0.011 g (34%). [α]_(D) =+45.3°,c=0.19 in methanol.

The opposite enantiomer was prepared in a similar manner fromN-tert-butyloxycarbonyl-D-alanine but the coupling reaction employedcarbonyl diimidazole. Carbonyl diimidazole (0.42 g, 2 mmol) was addedall at once to a stirred solution of N-tert-butyloxycarbonyl-D-alanine(0.76 g, 2 mmol) in methylene chloride (80 ml). The mixture was stirred1 hour; then Example 3 title product (0.366 g, 1 mmol) was added all atonce and the reaction stirred overnight. The mixture was diluted withmethylene chloride and extracted with aqueous bicarbonate. The organicphase was dried, concentrated and flash chromatographed on silica gel(2×7 inches). Elution with 25% ethyl acetate/hexane followed by 50%ethyl acetate/hexane gave 0.13 g of the desired diastereomer,recrystallized from ethyl acetate/hexane to yield 0.077 g of purifiedmaterial; m.p. 187°-188° C. [α]_(D) =-64.1°, c=0.17 in methanol. Thiswas hydrolyzed with methanolic sodium methoxide as above to give presenttitle product in 85% yield; [α].sub. D =-40.5°, c=0.21 in methanol.Continued elution of the above flash chromatography gave the otherdiastereomer contaminated with the first product.

EXAMPLE 19 7-Fluoro-5-[2-(4-hydroxy-4-phenylpiperidino)propionyl]-2-(1H,3H)-indolone

A mixture of 7-fluoro-5-(2-chloropropionyl) -2(1H,3H)-indolone (1.0 g,4.14 mmol), 4-hydroxy -4-phenylpiperidine (0.74 g, 4.17 mmol) andtriethylamine (1.2 ml, 8.6 mmol) in anhydrous dimethylformamide washeated to between 70 and 90° C. for 3 hours. The mixture was poured into1N aqueous LiCl and extracted with two portions of ethyl acetate. Thecombined organic phase was washed with 1N HCl, water and brine. Theorganic phase was dried over magnesium sulfate, filtered andconcentrated to 1.6 g of a reddish solid. The crude product was purifiedby flash chromatography on silica gel (2×4 inches, 50% ethylacetate/hexane eluent) to yield 0.58 g of the desired product. Thisproduct was further purified by recrystallization fromacetonitrile/ether to give 0.2 g of light yellow solid; m.p. 197°-199.5°C. NMR (DMSO-d₆) 11.25 (s, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.82 (s, 1H),7.42 (d, J=7.2 Hz, 2H), 7.28 (t, J=7.4 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H),4.76 (s, 1H), 4.25 (q, J=6.6 Hz, 1H), 3.66 (s, 2H), 2.88-2.63 (m, 2H),2.60-2.55 (m, 1H), 2.49-2.38 (m, 1H), 1.88 (dt, J=12.2, 4.3 Hz, 1H),1.77-1.49 (m, 3H), 1.16 (d, J=6.6 Hz, 3H). The mother liquors wererechromatographed to afford another 0.15 g of product for a total yieldof 0.35 g (22%).

Analysis calculated for C₂₂ H₂₃ FN₂ O₃ : C, 69.09; H, 6.06; N, 7.32.

Found: C, 68.36; H, 5.85; N, 7.31.

EXAMPLE 20 7-Fluoro-5-[2S*-(4-hydroxy-4-phenylpiperidino)-1S*-hydroxypropyl]-2(1H,3H)-indolone

Sodium borohydride (0.033 g, 0.872 mmol) was dissolved in absoluteethanol (3 ml) and the ketone product from the above reaction (0.3 g,0.78 mmol) was added all at once as a solid. The reaction was furtherdiluted with 10 ml of ethanol. The mixture was stirred under nitrogenfor 2 hours. The excess hydride was quenched with water and the mixturewas concentrated. The residue was partitioned between ethyl acetate andwater. The phases were separated and the organic layer was washed withbrine, dried over magnesium sulfate and concentrated to a glassy solid.This material was flash chromatographed on silica gel (1×4 inches).Elution with 50% ethyl acetate/hexane and then 100% ethyl acetate gave0.2 g of white solid. Further purification by recrystallization fromacetonitrile/ethyl acetate gave 0.1 g (33%) of product as a whitepowder; m.p. 225°-227° C. NMR (DMSO-d₆) 10.83 (br s, 1H), 7.54 (d, J=7.3Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.07 (t, J=5,3Hz, 2H), 5.09 (br s, 1H), 4.82 (s, 1H), 4.26 (d, J=9.3 Hz, 1H), 3.56 (s,2H), 2.97 (t, J=10.6 Hz, 1H), 2.62-2.56 (m, 4H), 2.12-1.92 (m, 2H), 1.63(br d, J=12.9 Hz, 2H), 0.74 (d, J=6.6 Hz, 3H).

Analysis calculated for C₂₂ H₂₅ FN₂ O₃ : C, 68.73; H, 6.55; N, 7.29.

Found: C, 68.53; H, 6.31; N, 7.13.

EXAMPLES 21-29

By the methods of the preceding examples, the following additionalcompounds were prepared (showing yield in final step, melting point andsolvent from which isolated).

21. 6-[1S*-Hydroxy-2S*(4-hydroxy-4-(4-methylphenyl)piperidino)propyl]-3,4-dihydro-2(1H)-quinolone; 4%; m.p. greater than250° C. (ethanol).

22.6-Chloro-5-[1S*-hydroxy-2S*(4-hydroxy-4-phenylpiperidino)propyl]-2(1H,3H)-indolone;1.7%; m.p. 200°-203° C. (ether).

23.5-[1S*-Hydroxy-2S*-(3-phenylthio-8-azabicyclo[3.2.1]-oct-8-yl)propyl-2(1H,3H)-indolone;12%; m.p. 159°-160° C. (ethyl acetate/acetonitrile).

24.5-[1R*-Hydroxy-2S*-(3-phenylthio-8-azabicyclo[3.2.1]-oct-8-yl)propyl-2(1H,3H)-indolone;7%; m.p. 211°-212° C. (ethyl acetate/acetonitrile).

25.7-Fluoro-5-[1S*-hydroxy-2S*(4-hydroxy-4-phenylpiperidino)propyl]-2(1H,3H)-indolone;33%; m.p. 225°-227° C. (ethyl acetate/acetonitrile).

26.4-Chloro-5-[1S*-hydroxy-2S*(4-hydroxy-4-phenylpiperidino)propy.1]-2(1H,3H)-indolone;31%; m.p. 231°-233° C. (ethanol/ether).

27.4-Chloro-5-[1R*-hydroxy-2S*(4-hydroxy-4-phenylpiperidino)propyl]-2(1H,3H)-indolone;14%; m.p. 213.5°-218° C. (ethanol/ether).

28. 5-[1S*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidino)propyl]-7-methyl-2(1H,3H)-indolone; 14%; m.p. 227.5°-230° C.(ethanol/dimethylsulfoxide).

29. 5-[1S*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidino)propyl]-4-methyl-2(1H,3H)-indolone; 22%; m.p. 241°-242° C.(ethanol/dimethylsulfoxide).

PREPARATION 1 5-Cyano-1-(p-toluenesulfonyl)indole

Sodium hydride (8.4 g, 210 mmol) was washed twice with hexane and thensuspended in tetrahydrofuran (500 ml). 5-Cyanoindole (20 g, 140 mmol) intetrahydrofuran (200 ml) was added dropwise. The resulting mixture wasstirred at ambient temperature for 1 hour and then p-toluenesulfonylchloride (26.7 g, 140 mmol) in tetrahydrofuran (200 ml) was added. Thereaction was stirred 3 hours more followed by addition of water. Thephases were separated and the aqueous phase was extracted twice withethyl acetate. The combined organic phase was washed with brine, driedover calcium sulfate and concentrated. The residue was recrystallizedfrom ether to afford 29.97 g, 72% of title product; m.p. 129°-131° C.;NMR 8.04 (d, J=8.5 Hz, 1H), 7.85 (d, J=1 Hz, 1H), 7.75 (d, J=9 Hz, 2H),7.67 (d, J=3.5 Hz, 1H), 7.53 (m, 1H), 7.23 (m, 2H), 6.68 (d, J=3.5 Hz,1H), 2.34 (s, 3H). IR(CHCl₃ solution) 2225, 1597, 1453, 1380, 1289,1266, 1169, 1138, 1123, 1089 (shoulder), 990. FAB HRMS calcd for C₁₆ H₁₃N₂ O₂ S(MH⁺): 297.0669. Observed m/e: 297.0685.

PREPARATION 2 5-Propionyl-1-(p-toluenesulfonyl)indole

The product of the preceding Preparation (11.4 g, 40 mmol) was dissolvedin dry toluene (760 ml) and chilled to 0° C. Ethylmagnesium bromide (14ml, 42 mmol, 3 M) in 40 ml of dry toluene was added dropwise. Themixture was warmed to 58° C. for 24 hours, cooled, and quenched withwater (60 ml) and 1N HCl (60 ml) with 0.5 hour stirring. The phases wereseparated and the aqueous layer was extracted 3 times with ethylacetate. The combined organic phase was washed with brine, dried overcalcium sulfate and concentrated. The residue was recrystallized fromethyl acetate to afford 6.8 g, 64% of present title product as a yellowsolid; m.p. 162°-164° C. NMR 8.16 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.5 Hz,1H), 7.94 (dd, J=1.5, 8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.62 (d,J=3.5 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), 6.72 (d, J=3.5 Hz, 1H), 3.02 (q,J=7 Hz, 2H), 2.33 (s, 3H), 1.21 (t, J=7 Hz, 3H).

PREPARATION 3 5-(2-Bromopropionyl)-1-(p-toluenesulfonyl)indole

The product of the preceding Preparation (2.0 g, 6.12 mmol) wasdissolved in chloroform (60 ml) and added dropwise to a suspension ofcupric bromide (2.1 g, 9.4 mmol) in ethyl acetate (60 ml). The resultingmixture was refluxed overnight. The reaction was cooled and filteredthrough a celite pad and concentrated. The residue was recrystallizedfrom ethyl acetate/hexane to afford 1.70 g, 69% of present title productas a brown solid. NMR analysis of this material showed it to be a 83/17mixture of product and starting material which was used in the couplingreaction without further purification. NMR signals of the product: 8.22(d, J=1.5 Hz, 1H), 8.04-7.91 (m, 2H), 7.77-7.73 (m, 2H), 7.62 (d, J=4Hz, 1H), 7.24-7.19 (m, 2H), 6.73 (d, J=4 Hz, 1H), 5.31 (q, J=6.5 Hz,1H), 2.32 (s, 3H), 1.87 (d, J=6.5 Hz, 3H).

PREPARATION 4 O-Methanesulfonyltropine

Tropine (14.2 g, 100 mmol) was dissolved in CH₂ Cl₂ (210 ml) andtriethylamine (23 ml, 160 mmol) was added. Methanesulfonyl chloride (9.3ml, 120 mmol) was added rapidly dropwise which caused the methylenechloride solution to reflux gently. The mixture was stirred one hourfurther; then extracted with cold 0.5 molar sodium hydroxide, water, andbrine, dried by filtration through phase separating paper andconcentrated to yield 13.8 g (65%) of title product as a yellow solid.NMR 4.88 (t, J=5 Hz, 1H), 3.10-3.05 (m, 2H), 2.94 (s, 3H), 2.22 (s, 3H),2.20-2.10 (m, 2H), 2.02-1.88 (m, 6H).

PREPARATION 5 3-Phenylthio-8-methyl-8-azabicyclo[3.2.1]octane

NaH (60% in oil; 2.77 g, 69 mmol) was washed with hexane (3x) and thensuspended in tetrahydrofuran (300 ml). Thiophenol (6.5 ml, 63 mmol) intetrahydrofuran (25 ml) was added dropwise over 5 minutes. The milkywhite suspension which formed, with hydrogen evolution, was stirred 10minutes and then O-methanesulfonyltropine (13.8 g, 63 mmol in 25 ml oftetrahydrofuran) was added all at once. The mixture was refluxedovernight, cooled and filtered through diatomaceous earth with etherwash. The filtrate was diluted with ethyl acetate and washed with cold1M NaOH, water, and brine, dried (CaSO₄) and concentrated to yield 11.48g (78%) of title product as a yellow solid. NMR 7.50-7.18 (m, 5H),3.32-3.21 (m, 1H), 3.15-3.09 (m, 2H), 2.25 s, 3H), 2.02-1.94 (m, 2H),1.79-1.72 (m, 4H), 1.60-1.51 (m, 2H); ¹³ C-NMR 134.8, 132.3, 128.8,126.9, 61.16, 39.21, 38.38, 37.72, 26.42.

By the same method, 4-chlorothiophenol was converted to3-(4-chlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]-octane.

PREPARATION 63-Phenylthio-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo[3.2.1]octane

Title product of the preceding Preparation (11.48 g, 49.3 mmol) and K₂CO₃ (0.75 g, 5.4 mmol) were mixed with benzene (200 ml) and2,2,2-trichloroethyl chloroformate (7.5 ml, 54.4 mmol) was addedrapidly. The reaction was refluxed 2 hours, cooled, filtered, andconcentrated. The orange oily residue was dissolved in CH₂ Cl₂, washedwith saturated NaHC₃ and then brine, dried (CaSO₄) and concentrated. Theresidue was purified by flash chromatography on silica gel (hexane andthen 5% ethyl acetate/hexane elution) to give first unreacted thiophenolfrom the previous reaction and then title product as a yellow oil (13 g,67%); NMR 7.42-7.23 (m, 5H), 4.72 (AB q, J=12 Hz, 2H), 4 35-4.30 (m,4H), 2.73 (heptet, J=6 Hz, 1H), 2.05-1.68 (m, 6H). The oil wassolidified by trituration with hexane; m.p. 83°-84.5° C.; Anal. C 48.47,H 4.58, N 3.49; calcd. C 48.68, H 4.60, N 3.55.

By the same method, the 4-chloro analog of the preceding Preparation wasconverted to3-(4-chlorophenylthio)-8-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-[3.2.1]octane.

PREPARATION 7 3-Phenylthio-8-azabicyclo[3.2.1]octane

Title product of the preceding Preparation (13.0 g, 33 mmol) wasdissolved in acetic acid (400 ml) and zinc dust (11 g, 168 mmol) wasadded. The mixture was heated to 100° C. overnight, then concentratedand the residue partitioned between CH₂ Cl₂ and saturated NaHCO₃. Theresulting emulsion was cleared by filtration through diatomaceous earth.The phases were separated and the organic layer was dried through phaseseparating filter paper and concentrated to yield 6.1 g (84%) of titleproduct as a yellow oil which solidified on standing; NMR 7.38-7.36 (m,2H), 7.29-7.20 (m, 3H), 3.52 (s, 2H), 3.36 (heptet, J=6 Hz, 1H),1.94-1.54 (m, 8H). ¹³ C-NMR 134.0, 132.43, 128.83, 127.06, 54.93, 40.81,39.01, 28.98.

By the same method, the 4-chloro analog of the preceding Preparation wasconverted to 3-(4-chlorophenylthio)-8-azabicyclo[3.2.1]octane.

PREPARATION 8 8-(2,2,2-Trichloroethoxycarbonyl)-3-endo-hydroxy-3-exo-phenyl-8-azabicyclo[3.2.1]octane

8-(2,2,2-Trichloroethoxycarbonyl)-8-azabicyclo -[3.2.1]octan-3-one (5.0g, 16.6 mmol) was dissolved in ether (450 ml) and phenylmagnesiumbromide (7.2 ml, 21.6 mmol, 3M in ether) was added dropwise over 5minutes with stirring. A white precipitate formed and the mixture wasstirred 30 minutes. Saturated ammonium chloride was added and themixture was concentrated. The residue was taken up in methylene chlorideand extracted with brine. The organic phase was further dried throughphase separating filter paper and concentrated to yield title product asa thick yellow oil (5.94 g, 94%). This material was used in the nextreaction without further purification.

The homologous 3-exo-benzyl derivative is prepared in like manner,substituting benzylmagnesium bromide for phenylmagnesium bromide.

PREPARATION 9 3-endo-Hydroxy-3-exo-phenyl-8-azabicyclo[3.2.1]octane

The entire title product from the preceding Preparation was dissolved intetrahydrofuran (100 ml) and added to a mixture of zinc dust (45 g, 688mmol) and 1M aqueous monopotassium phosphate (45 ml). The mixture wasstirred for 3 days. Water (100 ml) was then added and the pH wasadjusted to about 10 by the addition of solid sodium carbonate. Themixture was filtered through Oelite (TM) and concentrated to give 1.85 g(58%) of present title product as a white solid. Integration of the NMRspectrum for the bridgehead protons of this product showed it to be a92:8 mixture of the desired product (δ 3.6) and its 3-endo phenyl isomer(δ 3.85). This mixture was used as is for the coupling reactions asseparation of the coupled products is facile. ¹³ C-NMR (300 MHz,CDCl₃)delta: 150.42, 128.15, 126.57, 124.52, 73.33, 54.45, 46.62, 29.29.The minor isomer showed aliphatic ¹³ C signals at δ 54.92, 50.99, 30.33,30.16.

The homologous 3-exo-benzyl derivative is prepared in like manner.

I claim:
 1. A racemic or optically active compound of the formula##STR8## n is 0 or 1; m is 0 or an integer from 1-6;R, R¹ and R² areeach independently hydrogen or (C₁ -C₃)alkyl; R³ and R⁴ are takenseparately and are each hydrogen, or R³ and R⁴ are taken together andare ethylene; X is hydrogen, (C₁ -C₃)alkoxy or [(C₁ -C₃)alkoxy]-carbonyl; Y is CH₂ or oxygen; Z and Z¹ are each independentlyhydrogen, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy, fluoro, chloro or bromo; or apharmaceutically-acceptable acid addition salt thereof.
 2. A compound ofclaim 1 wherein R³ and R⁴ are taken separately and are each hydrogen. 3.A compound of claim 1 wherein m is 0 or 1, Z and Z¹ are each hydrogenand R² is hydrogen or methyl.
 4. A compound of claim 3 wherein R³ and R⁴are taken separately.
 5. A compound of claim 4 wherein R² is methylhaving the relative stereochemical formula ##STR9##
 6. A compound ofclaim 5 wherein A is ##STR10##
 7. A compound of claim 6 wherein n is 0.8. A compound of claim 7 wherein m is 1 and R and R¹ are each hydrogen.9. A compound of claim 7 wherein m is
 0. 10. The racemic compound ofclaim 9 wherein R and R¹ are each hydrogen.
 11. An optically activecompound of claim 9 wherein R and R¹ are each hydrogen.
 12. A compoundof claim 6 wherein n is 1 and Y is CH₂.
 13. A compound of claim 12wherein R and R¹ are each hydrogen and m is
 0. 14. A compound of claim 5wherein A is ##STR11##
 15. A compound of claim 14 wherein n is
 0. 16. Acompound of claim 15 wherein R and X are each hydrogen and m is
 0. 17. Acompound of claim 5 wherein A is ##STR12##
 18. A compound of claim 17wherein R and R¹ are each hydrogen and n and m are each
 0. 19. Acompound of claim 5 wherein A is ##STR13##
 20. A compound of claim 19wherein m is
 0. 21. A compound of claim 5 wherein A is ##STR14##
 22. Acompound of claim 21 wherein m is
 0. 23. A compound of claim 4 whereinR² is hydrogen.
 24. A compound of claim 23 wherein A is ##STR15##
 25. Acompound of claim 24 wherein n is
 0. 26. A compound of claim 25 whereinm is 0, and R and R¹ are each hydrogen.
 27. A compound of claim 25wherein m is 1, and R and R¹ are each hydrogen.
 28. A compound of claim23 wherein A is ##STR16##
 29. A compound of claim 28 wherein m is
 0. 30.A compound of claim 3 wherein R³ and R⁴ are taken together.
 31. Acompound of claim 30 wherein R² is methyl having the relativestereochemical formula ##STR17##
 32. A compound of claim 31 wherein A is##STR18## n is 0 and R and R¹ are each hydrogen.
 33. A pharmaceuticalcomposition comprising a neuroprotective amount of a compound of claim 1and a pharmaceutically-acceptable carrier.
 34. A pharmaceuticalcomposition comprising a neuroprotective amount of a compound of claim 4and a pharmaceutically-acceptable carrier.
 35. A pharmaceuticalcomposition comprising a neuroprotective amount of a compound of claim30 and a pharmaceutically-acceptable carrier.
 36. A method of treatingstroke, traumatic brain injury or a CNS degenerative disease in manwhich comprises treatment with a neuroprotective amount of a compound ofclaim
 1. 37. A method of treating stroke, traumatic brain injury or aCNS degenerative disease in man which comprises treatment with aneuroprotective amount of a compound of claim
 4. 38. A method oftreating stroke, traumatic brain injury or a CNS degenerative disease inman which comprises treatment with a neuroprotective amount of acompound of claim
 30. 39. A compound of the formula ##STR19## n is 0 or1; m is 0 or an integer from 1-6;R, R¹ and R² are each independentlyhydrogen or (C₁ -C₃)alkyl; R³ and R⁴ are taken separately and are eachhydrogen, or R³ and R⁴ are taken together and are ethylene; X ishydrogen, (C₁ -C₃)alkoxy or [(C₁ -C₃)alkoxy]carbonyl; Y is CH₂ oroxygen; Z and Z¹ are each independently hydrogen, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy, fluoro, chloro or bromo.
 40. A racemic or optically activecompound of the formula ##STR20## n is 0 or 1; R, R¹ and R² are eachindependently hydrogen or (C₁ -C₃)alkyl;R³ and R⁴ are taken separatelyand are each hydrogen, or R³ and R⁴ are taken together and are ethylene;X is hydrogen, (C₁ -C₃)alkoxy or [(C₁ -C₃)alkoxy]carbonyl; Y is CH₂ oroxygen; Z and Z¹ are each independently hydrogen, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy, fluoro, chloro or bromo; or a pharmaceutically-acceptableacid addition salt thereof.
 41. A compound of claim 40 wherein A is##STR21##
 42. A compound of claim 41 wherein R³ and R⁴ are takentogether.
 43. A compound of claim 42 wherein R² is methyl having therelative stereochemical formula ##STR22##
 44. A compound of claim 43wherein R and R¹ are each hydrogen and n is
 0. 45. A compound of claim44 wherein Z and Z¹ are each hydrogen or chloro.
 46. A pharmaceuticalcomposition comprising a neuroprotective amount of a compound of claim40 and a pharmaceutically-acceptable carrier.
 47. A method of treatingstroke, traumatic brain injury or a CNS degenerative disease in manwhich comprises treatment with a neuroprotective amount of a compound ofclaim
 40. 48. A compound of the formula ##STR23## n is 0 or 1; R, R¹ andR² are each independently hydrogen or (C₁ --C₃)alkyl;R³ and R⁴ are takenseparately and are each hydrogen, or R³ and R⁴ are taken together andare ethylene; X is hydrogen, (C₁ -C₃)alkoxy or [(C₁--C₃)alkoxy]carbonyl; Y is CH₂ or oxygen; Z and Z¹ are eachindependently hydrogen, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy, fluoro, chloro orbromo.
 49. A racemic or optically active compound of the formula##STR24## n is 0 or 1; R, R¹ and R² are each independently hydrogen or(C₁ -C₃)alkyl;X is hydrogen, (C₁ -C₃)alkoxy or [(C₁ -C₃)alkoxy]carbonyl;Y is CH₂ or oxygen; Z and Z¹ are each independently hydrogen, (C₁-C₃)alkyl, (C₁ -C₃)alkoxy, fluoro, chloro or bromo; or apharmaceutically-acceptable acid addition salt thereof.
 50. A compoundof claim 49 wherein A is ##STR25##
 51. A compound of claim 50 wherein Rand R¹ are each hydrogen.
 52. A compound of claim 51 wherein Z ishydrogen and Z¹ is hydrogen or chloro.
 53. A pharmaceutical compositioncomprising a neuroprotective amount of a compound of claim 49 and apharmaceutically-acceptable carrier.
 54. A method of treating stroke,traumatic brain injury or a CNS degenerative disease in man whichcomprises treatment with a neuroprotective amount of a compound of claim49.
 55. A compound of the formula ##STR26## wherein ##STR27## n is 0 or1; R, R¹ and R² are each independently hydrogen or (C₁ -C₃)alkyl;X ishydrogen, (C₁ -C₃)alkoxy or [(C₁ -C₃)alkoxy]carbonyl; Y is CH₂ oroxygen; Z and Z¹ are each independently hydrogen, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy, fluoro, chloro or bromo; or a pharmaceutically-acceptableacid addition salt thereof.